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Association between altered hippocampal oligodendrocyte number and neuronal circuit structures in schizophrenia: a postmortem analysis

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Abstract

In schizophrenia, decreased hippocampal volume, reduced oligodendrocyte numbers in hippocampal cornu ammonis (CA) subregions and reduced neuron number in the dentate gyrus have been reported; reduced oligodendrocyte numbers were significantly related to cognitive deficits. The hippocampus is involved in cognitive functions and connected to the hypothalamus, anterior thalamus, and cingulate cortex, forming the Papez circuit, and to the mediodorsal thalamus. The relationship between the volume of these interconnected regions and oligodendrocyte and neuron numbers in schizophrenia is unknown. Therefore, we used stepwise logistic regression with subsequent multivariate stepwise linear regression and bivariate correlation to analyze oligodendrocyte and neuron numbers in the posterior hippocampal subregions CA1, CA2/3, CA4, dentate gyrus, and subiculum and volumes of the hippocampal CA region, cingulum, anterior and mediodorsal thalamus and hypothalamus in postmortem brains of 10 schizophrenia patients and 11 age- and gender-matched healthy controls. Stepwise logistic regression identified the following predictors for diagnosis, in order of inclusion: (1) oligodendrocyte number in CA4, (2) hypothalamus volume, (3) oligodendrocyte number in CA2/3, and (4) mediodorsal thalamus volume. Subsequent stepwise linear regression analyses identified the following predictors: (1) for oligodendrocyte number in CA4: (a) oligodendrocyte number in CA2/3, (b) diagnostic group, (c) hypothalamus volume, and (d) neurons in posterior subiculum; (2) for hypothalamus volume: (a) mediodorsal thalamus volume; (3) for oligodendrocyte number in CA2/3: oligodendrocyte number (a) in posterior CA4 and (b) in posterior subiculum; (4) for mediodorsal thalamus volume: volumes of (a) anterior thalamus and (b) hippocampal CA. In conclusion, we found a positive relationship between hippocampal oligodendrocyte number and the volume of the hypothalamus, a brain region connected to the hippocampus, which is important for cognition.

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References

  1. Jablensky A (1995) Schizophrenia: recent epidemiologic issues. Epidemiol Rev 17:10–20

    Article  CAS  Google Scholar 

  2. Häfner H, an der Heiden W (2007) Course and outcome of schizophrenia. In: Hirsch SR, Weinberger D (eds) Schizophrenia. Wiley-Blackwell, Oxford, pp 101–141

    Google Scholar 

  3. Falkai P, Schmitt A, Cannon TD (2011) Pathophysiology of Schizophrenia. In: Hirsch SR, Weinberger D (eds) Schizophrenia. Wiley-Blackwell, Oxford, pp 31–65

    Chapter  Google Scholar 

  4. Schmitt A, Steyskal C, Bernstein H-G et al (2009) Stereologic investigation of the posterior part of the hippocampus in schizophrenia. Acta Neuropathol 117:395–407. https://doi.org/10.1007/s00401-008-0430-y

    Article  PubMed  Google Scholar 

  5. Falkai P, Malchow B, Wetzestein K et al (2016) Decreased oligodendrocyte and neuron number in anterior hippocampal areas and the entire hippocampus in schizophrenia: a stereological postmortem study. Schizophr Bull 42(Suppl 1):S4–S12. https://doi.org/10.1093/schbul/sbv157

    Article  PubMed  PubMed Central  Google Scholar 

  6. Falkai P, Honer WG, David S et al (1999) No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol 25:48–53

    Article  CAS  Google Scholar 

  7. van Kesteren CFMG, Gremmels H, de Witte LD et al (2017) Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry 7:e1075. https://doi.org/10.1038/tp.2017.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hof PR, Haroutunian V, Friedrich VL et al (2003) Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 53:1075–1085

    Article  CAS  Google Scholar 

  9. Cassoli JS, Guest PC, Malchow B et al (2015) Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules. NPJ Schizophr 1:15034. https://doi.org/10.1038/npjschz.2015.34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Falkai P, Steiner J, Malchow B et al (2016) Oligodendrocyte and interneuron density in hippocampal subfields in schizophrenia and association of oligodendrocyte number with cognitive deficits. Front Cell Neurosci 10:78. https://doi.org/10.3389/fncel.2016.00078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Catani M, Dell’acqua F, Thiebaut de Schotten M (2013) A revised limbic system model for memory, emotion and behaviour. Neurosci Biobehav Rev 37:1724–1737. https://doi.org/10.1016/j.neubiorev.2013.07.001

    Article  PubMed  Google Scholar 

  12. Shah A, Jhawar SS, Goel A (2012) Analysis of the anatomy of the Papez circuit and adjoining limbic system by fiber dissection techniques. J Clin Neurosci 19:289–298. https://doi.org/10.1016/j.jocn.2011.04.039

    Article  PubMed  Google Scholar 

  13. Delay J, Brion S (1969) Le syndrome de Korsakoff. Masson, Paris

    Google Scholar 

  14. Gaffan D (1992) The role of the hippocampus–fornix–mammillary system in episodic memory. In: Squire LR, Butters N (eds) Neuropsychology of memory, 2nd edn. Guilford Press, New York, pp 336–346

    Google Scholar 

  15. Aggleton JP, Brown MW (1999) Episodic memory, amnesia, and the hippocampal–anterior thalamic axis. Behav Brain Sci 22:425–444 (discussion 444–489)

    Article  CAS  Google Scholar 

  16. Russchen FT, Amaral DG, Price JL (1987) The afferent input to the magnocellular division of the mediodorsal thalamic nucleus in the monkey, Macaca fascicularis. J Comp Neurol 256:175–210. https://doi.org/10.1002/cne.902560202

    Article  CAS  PubMed  Google Scholar 

  17. Saunders RC, Mishkin M, Aggleton JP (2005) Projections from the entorhinal cortex, perirhinal cortex, presubiculum, and parasubiculum to the medial thalamus in macaque monkeys: identifying different pathways using disconnection techniques. Exp Brain Res 167:1–16. https://doi.org/10.1007/s00221-005-2361-3

    Article  PubMed  Google Scholar 

  18. Mitchell AS, Chakraborty S (2013) What does the mediodorsal thalamus do? Front Syst Neurosci 7:37. https://doi.org/10.3389/fnsys.2013.00037

    Article  PubMed  PubMed Central  Google Scholar 

  19. Byne W, Buchsbaum MS, Mattiace LA et al (2002) Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia. Am J Psychiatry 159:59–65. https://doi.org/10.1176/appi.ajp.159.1.59

    Article  PubMed  Google Scholar 

  20. Cobia DJ, Smith MJ, Salinas I et al (2017) Progressive deterioration of thalamic nuclei relates to cortical network decline in schizophrenia. Schizophr Res 180:21–27. https://doi.org/10.1016/j.schres.2016.08.003

    Article  PubMed  Google Scholar 

  21. Avram M, Brandl F, Bäuml J, Sorg C (2018) Cortico-thalamic hypo- and hyperconnectivity extend consistently to basal ganglia in schizophrenia. Neuropsychopharmacology. https://doi.org/10.1038/s41386-018-0059-z

    Article  PubMed  PubMed Central  Google Scholar 

  22. Peters SK, Dunlop K, Downar J (2016) Cortico-striatal-thalamic loop circuits of the salience network: a central pathway in psychiatric disease and treatment. Front Syst Neurosci 10:104. https://doi.org/10.3389/fnsys.2016.00104

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bogerts B, Falkai P, Haupts M et al (1990) Post-mortem volume measurements of limbic system and basal ganglia structures in chronic schizophrenics. Initial results from a new brain collection. Schizophr Res 3:295–301

    Article  CAS  Google Scholar 

  24. Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831. https://doi.org/10.1016/j.neuroscience.2004.08.050

    Article  CAS  PubMed  Google Scholar 

  25. Bernstein H-G, Dobrowolny H, Bogerts B et al (2018) The hypothalamus and neuropsychiatric disorders: psychiatry meets microscopy. Cell Tissue Res. https://doi.org/10.1007/s00441-018-2849-3

    Article  PubMed  Google Scholar 

  26. Walker EF, Diforio D (1997) Schizophrenia: a neural diathesis-stress model. Psychol Rev 104:667–685

    Article  CAS  Google Scholar 

  27. Walder DJ, Walker EF, Lewine RJ (2000) Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia. Biol Psychiatry 48:1121–1132

    Article  CAS  Google Scholar 

  28. Havelka D, Prikrylova-Kucerova H, Prikryl R, Ceskova E (2016) Cognitive impairment and cortisol levels in first-episode schizophrenia patients. Stress 19:383–389. https://doi.org/10.1080/10253890.2016.1193146

    Article  CAS  PubMed  Google Scholar 

  29. Kumari V, Fannon D, Ffytche DH et al (2010) Functional MRI of verbal self-monitoring in schizophrenia: performance and illness-specific effects. Schizophr Bull 36:740–755. https://doi.org/10.1093/schbul/sbn148

    Article  PubMed  Google Scholar 

  30. Hallock HL, Wang A, Griffin AL (2016) Ventral midline thalamus is critical for hippocampal–prefrontal synchrony and spatial working memory. J Neurosci 36:8372–8389. https://doi.org/10.1523/JNEUROSCI.0991-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Griffin AL (2015) Role of the thalamic nucleus reuniens in mediating interactions between the hippocampus and medial prefrontal cortex during spatial working memory. Front Syst Neurosci 9:29. https://doi.org/10.3389/fnsys.2015.00029

    Article  PubMed  PubMed Central  Google Scholar 

  32. Parnaudeau S, Taylor K, Bolkan SS et al (2015) Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior. Biol Psychiatry 77:445–453. https://doi.org/10.1016/j.biopsych.2014.03.020

    Article  PubMed  Google Scholar 

  33. Vostrikov VM, Uranova NA, Orlovskaya DD (2007) Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders. Schizophr Res 94:273–280. https://doi.org/10.1016/j.schres.2007.04.014

    Article  PubMed  Google Scholar 

  34. Vostrikov V, Orlovskaya D, Uranova N (2008) Deficit of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia. World J Biol Psychiatry 9:34–42. https://doi.org/10.1080/15622970701210247

    Article  PubMed  Google Scholar 

  35. Kolomeets NS, Uranova NA (2019) Reduced oligodendrocyte density in layer 5 of the prefrontal cortex in schizophrenia. Eur Arch Psychiatry Clin Neurosci 269:379–386. https://doi.org/10.1007/s00406-018-0888-0

    Article  PubMed  Google Scholar 

  36. Fünfschilling U, Supplie LM, Mahad D et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485:517–521. https://doi.org/10.1038/nature11007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martins-de-Souza D, Maccarrone G, Wobrock T et al (2010) Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia. J Psychiatr Res 44:1176–1189. https://doi.org/10.1016/j.jpsychires.2010.04.014

    Article  PubMed  Google Scholar 

  38. Guest PC, Iwata K, Kato TA et al (2015) MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia. Front Cell Neurosci 9:180. https://doi.org/10.3389/fncel.2015.00180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bernstein H-G, Krause S, Krell D et al (2007) Strongly reduced number of parvalbumin-immunoreactive projection neurons in the mammillary bodies in schizophrenia: further evidence for limbic neuropathology. Ann N Y Acad Sci 1096:120–127. https://doi.org/10.1196/annals.1397.077

    Article  CAS  PubMed  Google Scholar 

  40. Micheva KD, Wolman D, Mensh BD et al (2016) A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons. Elife 5:e15784. https://doi.org/10.7554/eLife.15784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schmitt A, Simons M, Cantuti-Castelvetri L, Falkai P (2019) A new role for oligodendrocytes and myelination in schizophrenia and affective disorders? Eur Arch Psychiatry Clin Neurosci 269:371–372. https://doi.org/10.1007/s00406-019-01019-8

    Article  PubMed  Google Scholar 

  42. Makinodan M, Rosen KM, Ito S, Corfas G (2012) A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337:1357–1360. https://doi.org/10.1126/science.1220845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Jacquie Klesing, BMedSci (Hons), Board-certified Editor in the Life Sciences (ELS), for editing assistance with the manuscript. Ms. Klesing received compensation for her work from the LMU Munich, Germany.

Funding

This research was funded by the following grants from the German Research Foundation (DFG): Klinische Forschergruppe (KFO) 241 and PsyCourse to PF (FA241/16-1). Furthermore, the study was supported by the European Commission under the Sixth Framework Programme (BrainNet Europe II, LSHM-CT-2004-503039) and Else Kröner-Fresenius-Stiftung (Foundation) to FR, PF, and AS.

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Author notes

  1. Peter Falkai, Florian Raabe, Johann Steiner and Andrea Schmitt have been contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University Munich, Nussbaumstrasse 7, 80336, Munich, Germany

    Peter Falkai, Florian Raabe, Thomas Schneider-Axmann, Berend Malchow, Laura Tatsch, Verena Huber, Lenka Slapakova & Andrea Schmitt

  2. International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Kraepelinstr. 2-10, 80804, Munich, Germany

    Florian Raabe

  3. Department of Psychiatry and Psychotherapy, University of Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany

    Bernhard Bogerts, Henrik Dobrowolny & Johann Steiner

  4. Department of Psychiatry and Psychotherapy, University of Jena, Philosophenweg 3, 07743, Jena, Germany

    Berend Malchow

  5. Department of Neuroanatomy, LMU Munich, Pettenkoferstrasse 11, 80336, Munich, Germany

    Christoph Schmitz

  6. German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17, 81377, Munich, Germany

    Ludovico Cantuti-Castelvetri & Mikael Simons

  7. Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany

    Mikael Simons

  8. Institute of Neuronal Cell Biology, Technical University Munich, 80805, Munich, Germany

    Mikael Simons

  9. Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovidio Pires de Campos 785, São Paulo, SP, 05453-010, Brazil

    Andrea Schmitt

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  1. Peter Falkai
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Correspondence to Andrea Schmitt.

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Conflict of interest

FR, B.M, TS-A, LT, VH, LS, HD, BB, MS, and CS declare no conflicts of interest. PF has been an honorary speaker for AstraZeneca, Bristol Myers Squibb, Lilly, Essex, GE Healthcare, GlaxoSmithKline, Janssen Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Takeda and has been a member of the advisory boards of Janssen-Cilag, AstraZeneca, Lilly, and Lundbeck. AS was honorary speaker for TAD Pharma and Roche and a member of Roche advisory boards. JS was honorary speaker and advisory board member for Janssen-Cilag.

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Falkai, P., Raabe, F., Bogerts, B. et al. Association between altered hippocampal oligodendrocyte number and neuronal circuit structures in schizophrenia: a postmortem analysis. Eur Arch Psychiatry Clin Neurosci 270, 413–424 (2020). https://doi.org/10.1007/s00406-019-01067-0

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  • DOI: https://doi.org/10.1007/s00406-019-01067-0

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